Chapter 16 Amenorrhea

INTRODUCTION

Disorders of the menstrual cycle are one of the most common reproductive problems seen in a gynecologic practice. The absence of a menstrual period is a frequent symptom of underlying pathology of either the reproductive tract or the hypothalamic-pituitary-ovarian axis. This chapter examines both primary and secondary amenorrhea. Although some of the etiologies for these two conditions overlap, the most common causes and thus the diagnostic approaches used for the two are very different. For this reason, primary and secondary amenorrhea are considered separately in terms of etiology, diagnosis, and management. Each section concludes with a comprehensive diagnostic approach.

DEFINITIONS

In common medical usage, amenorrhea refers to the abnormal cessation of menses.¹ Physiologic amenorrhea exists before puberty, during pregnancy and lactation, and after menopause. However, these physiologic causes are not included in the standard amenorrhea classifications.

Amenorrhea can be divided into two major groups based on presentation: primary or secondary amenorrhea (Table 16-1).^2,³ Although many of the causes of primary and secondary amenorrhea are similar, the most likely causes, and thus the diagnostic approach, are distinct.

Table 16-1 Definitions of Primary and Secondary Amenorrhea

Primary Amenorrhea

Primary amenorrhea is the absence of menstruation in a woman who has never menstruated. Because children do not normally menstruate before puberty, the age at which primary amenorrhea is diagnosed depends on the presence or absence of secondary sexual characteristics. In the absence of increased growth or development of secondary sexual characteristics, primary amenorrhea is diagnosed when the patient has no menses by age 13. In the presence of normal growth and development of secondary sexual characteristics, the diagnosis of primary amenorrhea is reserved for patients who have no menstruation by age 15. The incidence of primary amenorrhea in the United States is less than 0.1%. The majority of patients with primary amenorrhea will be found to have either gonadal dysgenesis (49%) or müllerian agenesis (16%).⁴

Secondary Amenorrhea

Secondary amenorrhea refers to cessation of menses after establishment of menstruation for reasons other than pregnancy, lactation, or menopause. By convention, the diagnosis is applied after menses have been absent for a length of time equivalent to at least 3 of the previous menstrual cycle intervals or 6 months.

The incidence of secondary amenorrhea not due to pregnancy, lactation, or menopause is approximately 4%.^5,⁶ Although the list of causes for amenorrhea is quite extensive (Table 16-2), it appears that this list will continue to grow or be modified as more sophisticated genetic testing becomes available and the genetic understanding of human disease expands. The majority of patients with amenorrhea will have premature ovarian failure, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome (PCOS).

Table 16-2 Classification of Amenorrhea, Both Primary and Secondary ³

VI. Multifactorial causes

A. Polycystic ovary syndrome

Classification

The most widely accepted classification of amenorrhea was published by the World Health Organization (WHO) and divides amenorrhea into three groups (Table 16-3).³ This WHO amenorrhea classification is designed to help the practicing clinician summarize the causes of amenorrhea to assist in evaluating the condition. Group I include individuals who lack endogenous estrogen production, in association with normal or low follicle-stimulating hormone (FSH) levels, and no evidence of hypothalamic-pituitary pathology or elevated prolactin levels. Group II is associated with evidence of estrogen production and normal levels of prolactin and FSH. Finally, Group III involves elevated serum FSH levels that indicate gonadal failure.⁷ Although amenorrhea can occur among patients with sexual ambiguity or virilization, it is rarely the cause for initial consultation.⁸

Table 16-3 World Health Organization (WHO) Classification of Amenorrhea

PRIMARY AMENORRHEA

The etiologies of primary amenorrhea are multiple and diverse (Tables 16-4 and 16-5). The four most common causes of primary amenorrhea have been reported to be the following:⁴

(1) Gonadal dysgenesis (almost half of all cases)

(2) Müllerian agenesis (i.e., congenital absence of the uterus and vagina)

(3) Hypothalamic disorders, including those related to exercise and nutrition

(4) Constitutional delay of puberty

Table 16-4 Common Causes of Primary Amenorrhea

Category	Frequency
Normal Secondary Sexual Development	(∼1/3 of total)
Müllerian agenesis	10%
Androgen insensitivity	9%
Constitutional delay	8%
Outlet obstruction (e.g., vaginal septum, imperforate hymen)	3%
Absent Secondary Sexual Development	(∼2/3 of total)
High FSH (gonadal dysgenesis)
Abnormal karyotype (e.g., 46,XO, mosaic)	20%
46,XX	15%
46,XY	5%
Low FSH
Hypothalamic disorders	8%
Constitutional delay	10%
Hyperandrogenic conditions (e.g., PCOS, CAH)	6%
Pituitary adenomas	5%

Adapted from Practice Committee of ASRM: Current evaluation of amenorrhea. Fertil Steril 82(Suppl 1):33-S39, 2004.

Table 16-5 Genital Tract Abnormalities Associated with Amenorrhea

Other causes of primary amenorrhea, while less common, include outflow obstructions (e.g., imperforate hymen, transverse vaginal septum), androgen insensitivity syndrome, and inborn defects in gonadotropin secretion or response. Several of these are examined in this chapter; others are discussed in separate chapters.

Gonadal Dysgenesis

The term gonadal dysgenesis is used globally to refer to all forms of abnormal gonads, which can occur in individuals with normal karyotypes (46,XX; 46,XY) as well as a variety of abnormal or mosaic states, most commonly Turner’s syndrome (45,XO). The gonads are usually streaks of fibrous tissue.

Pure Gonadal Dysgenesis

Pure gonadal dysgenesis refers to phenotypically female individuals with streak gonads and normal female external genitalia and normal müllerian structures whose karyotype can be either 46,XY (Swyer syndrome) or 46,XX. This heterogeneous condition results from a structural abnormality on the Y chromosome, a mutation in the SRY gene, or a mutation in an autosomal gene.

Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis refers to individuals with defective gonadal development secondary to a chromosomal mosaic variant. Their karyotypes show partial sex chromosome monosomy with an absence or abnormality of the second sex chromosome, with 45,XO/46,XY being the most common. Their phenotypes range from phenotypic female to pseudohermaphrodite to phenotypic male, depending on the ratio of 45,XO cells to those with normal (46,XX or 46,XY) karyotypes in each gonad. These patients present with abnormal sex differentiation. There can be a streak gonad on one side and a dysgenetic gonad or normal testicle on the other and with concurrent ipsilateral Wolffian or müllerian development. Most of these individuals have short stature, and one third will show characteristics of Turner’s syndrome.

The majority of patients with gonadal dysgenesis will never have menses. This group of patients make up 40% of cases of primary amenorrhea, and 40% will have an abnormal karyotype. This abnormal karyotype will be Turner’s syndrome (46,XO) 50% of the time and a mosaicism such as XO/XY 25% of the time.

Patients who present with gonadal dysgenesis and a normal karyotype need to be assessed for a variety of other conditions, such as neurosensory deafness and fragile X syndrome. These clinical associations are particularly true when familial premature ovarian failure is identified.⁹

General Principles of X Chromosome Genetic Disorders

Short stature is the result of a mutation of the SHOX gene (short stature homeobox-containing gene). The gene is located on the pseudoautosomal region of the X chromosome, and two normal copies are required for the development of normal stature.

Isolated deletions of portions of the X chromosome have also been reported. Deletions affecting Xp11 result in ovarian failure in about half of women. Deletions involving the q arm of the X chromosome also usually result in ovarian failure. Even in those who achieve normal menstruation, fertility is rare.

When the deletion on the X chromosome is more distal (Xp21 region), the phenotype is generally milder. However, secondary amenorrhea or infertility is common. Most women with Xp deletions are short, regardless of their ovarian function, and present with a Turner’s syndrome-like phenotype. The molecular mechanism responsible for ovarian failure in these cases is due to loss of a putative ovarian determinant gene necessary for ovarian development, increasing follicular atresia, but not to the extent of that observed in patients with Turner’s syndrome.

Translocations of the X chromosome, although extremely rare, may cause amenorrhea depending on the location of breakpoints. In a balanced X translocation one X chromosome is normal, and the other is an X autosome translocation chromosome. X inactivation is not usually random so that the normal X is usually inactivated. If the translocated chromosome were inactivated, the autosome would also be inactivated, making the karyotype lethal. Nearly all males and half of the females with X autosome translocations are sterile.¹⁰

Turner’s Syndrome

It is known that specific genes in the X chromosome are essential for normal functioning of the ovaries.¹¹ It appears that both X chromosomes with normally functioning genes need to be present in the oocytes to prevent the formation of a streak gonad.

Turner’s syndrome (45,XO) is the most common cause of gonadal dysgenesis. It is usually caused by nondisjunction of the sex chromosomes and occurs in approximately 1 out of 2500 live births. In some cases, Turner’s syndrome occurs in patients with normal karyotypes (46,XX) when a genetic abnormality results in one of the X chromosomes not being fully functional.

The characteristic physical features common to females with Turner’s syndrome include short stature, somatic abnormalities (webbed neck, shield chest, increased angle at the elbow known as cubitus valgus, cardiovascular abnormalities), and prepubertal status associated with elevated gonadotropins.¹² Patients with Turner’s syndrome require special attention to the autoimmune disorders and renal anomalies that are frequently found with the condition. All patients with Turner’s syndrome should seek expert cardiology consultation and screening, including chest X-ray and echocardiography, at the time of diagnosis. Annual cardiac examinations, including evaluation of blood pressure, and repeated screening at 3- to 5-year intervals if the initial screening reveals no abnormalities. When the cardiac echo is abnormal or the ascending aorta cannot be visualized, magnetic resonance imaging (MRI) of the chest should be performed in all patients.¹²

Due to the absence of one of the X chromosomes, these patients have streak gonads with complete lack of ovarian follicle development. The absence of sex hormone production from the ovary in early adolescence results in the absence of puberty and primary amenorrhea.

Patients with variations of the syndrome can present with some clinical features but not all of the characteristic physical findings. For this reason, Turner’s syndrome should be suspected in every adolescent with primary amenorrhea, sexual infantilism, and poor growth during the teenage years. If the serum FSH is elevated in such a patient, a karyotype should be obtained. Even if the FSH is normal, a karyotype should be obtained to rule out mosaicism in adolescents with poor growth after puberty (i.e., <5 feet tall).

Disorders of the Genital Tract

Disorders of the genital tract encompass both abnormalities of the müllerian system (uterus, fallopian tubes, and vagina) and abnormalities of the external genitalia. In adolescents with normal pubertal development and primary amenorrhea, a genital tract disorder will be found on physical examination in 15% of cases. Common disorders include müllerian agenesis, imperforate hymen, and transverse vaginal septum.

Müllerian Agenesis

Mullerian agenesis, also referred to as Mayer-Rokitansky-Küster-Hauser syndrome, is a condition in which all or part of the uterus and vagina are absent in the presence of otherwise normal female sexual characteristics. This diagnosis accounts for approximately 10% of cases associated with primary amenorrhea.¹⁵ In Finland, the incidence was calculated to be approximately 1 of every 5000 newborn girls.¹⁶ In müllerian agenesis, the ovaries are not affected and thus ovarian function is normal. Secondary sexual development and height are in a normal range.

The differential diagnosis of patients who present with primary amenorrhea and have a genital tract anomaly is summarized in Table 16-4. Partial development of the müllerian structures can lead to obstructed menses and painful distention of a hematocolpos, hematometra, or hematoperitoneum. It is important to separate müllerian agenesis from complete androgen insensitivity syndrome, because the vagina may be absent or short in both disorders.¹⁷

It is currently unknown why müllerian agenesis occurs, but likely causes are mutations of genes that are responsible for müllerian tract maintenance. Thus far, no mutations have been reported.¹⁸ It appears that the mode of inheritance is not autosomal dominant.¹⁹

Approximately 30% of patients will have urinary tract anomalies, such as pelvic kidney, horseshoe kidney, unilateral renal agenesis, hydronephrosis, and ureteral duplication. Another 10% to 12% will have skeletal anomalies mostly associated with the spine. There are also reports of absent digits and webbing or fusion of fingers or toes (syndactyly).

Although ultrasound could be an important aid in confirming the presence or absence of uterine structures, MRI is usually more definitive. Occasionally laparoscopic visualization is needed, because there is disagreement between MRI and laparoscopic findings.²⁰ If persistent chronic pelvic pain and symptoms associated with endometriosis are present, laparoscopy can usually aid in determining the location and potential removal of incompletely formed müllerian structures.

Outflow Obstructions

Imperforate hymen is the most frequent obstructive female genital tract anomaly, with an estimated frequency of approximately 0.1%. Imperforate hymen usually occurs sporadically, but familial cases have been reported.²¹ Although this entity can present in infants or children of any age as a mucocolpos, a bulging intact hymen with hematocolpos presenting at the time of menarche is not unusual. Hymenectomy effectively alleviates this problem.

A transverse vaginal septum is somewhat less common than an imperforate hymen, occurring in fewer than 1 in 20,000 females. The presentation and surgical treatment is similar to an imperforate hymen if the transverse vaginal septa is located in the lower third of the vagina. However, more than 80% are located in the middle and upper vagina. Diagnosis is usually made by ultrasound or MRI. When located in these areas, septa tend to be thicker, and surgery is more difficult. Surgical management is described in detail in Chapter 51.

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (formerly known as testicular feminization), is an X-linked recessive condition in which genotypic males (46,XY) develop into apparently phenotypic females who have no müllerian structures and intra-abdominal testes. The underlying cause is an abnormally functioning androgen receptor, which prevents normal masculinization. This syndrome will be identified in as many as 5% of all patients presenting with primary amenorrhea.¹⁷

In the case of complete androgen insensitivity syndrome, normal female external genitalia develop. Complete androgen insensitivity is uncommon, with a reported incidence as low as 1 in 60,000 live births. In cases of incomplete androgen insensitivity syndrome, the external genitalia can demonstrate a range of intersex abnormalities from mildly virilized female external genitalia to mildly undervirilized male external genitalia.

Evaluation of Androgen Insensitivity Syndrome

These patients usually present with a family history of scant pubic hair and the presence of inguinal masses. Other female family members should be evaluated for the same diagnosis.

Patients with the condition may have a eunuchoid habitus with long arms and large hands and feet. Although the breasts develop for the most part normally, they lack glandular tissue and the nipples are small with a pale areola.

On pelvic examination, the patients will have scant or absent pubic hair and a blind vagina that is no more than a few centimeters long. More than 50% of patients have inguinal hernias and underdeveloped labia minora. Laboratory evaluation will demonstrate a 46,XY karyotype and elevated total testosterone (in the normal male range).²² This distinguishes patients with androgen insensitivity syndrome from those with müllerian agenesis, who will have an XX karyotype and total testosterone in the normal female range.

Gonadal malignancies have been reported in the 20% range, but are rarely seen before age 20. Therefore, a typical plan of action for these patients is to wait, allowing them to reach their normal adult stature and full breast development, then perform bilateral laparoscopic gonadectomy after puberty has been reached.

Patients with lack of 17β-hydroxysteroid dehydrogenase activity also have impaired testosterone production and present clinically as incomplete androgen insensitivity. The treatment for both conditions is essentially the same.

Rare Causes of Primary Amenorrhea

Isolated Gonadotropin Deficiency

This disorder is characterized by a decrease or absence in endogenous gonadotropin-releasing hormone (GnRH) secretion, which results in very low to undetectable luteinizing hormone (LH) and FSH levels. Individuals with the disorder have incomplete development of secondary sexual characteristics, primary amenorrhea, eunuchoid features, and in some cases a decreased sense of smell or anosmia (Kallmann syndrome). Male patients with Kallmann syndrome have X-linked recessive idiopathic hypogonadotropic hypogonadism accompanied by anosmia caused by mutations in the KAL1 gene, localized to the pseudoautosomal region of Xp.^23,²⁴

The protein product of KAL1, anosmin, possesses neural cell adhesion molecule properties. Anosmin provides a guide for GnRH neurons and olfactory nerves to migrate from the olfactory placode across to the olfactory bulb. When anosmin is absent or defective, GnRH and olfactory neurons fail to synapse normally. The KAL1 gene escapes X inactivation and an inactive pseudogene is present on Yq. For individuals with anosmia or hyposmia, there is evidence of hypoplasia of the olfactory bulbs on MRI. No KAL1 gene mutations have been identified in females with idiopathic hypogonadotropic hypogonadism and anosmia, suggesting that other autosomal genes may be involved.²⁵

LH Receptor Abnormalities

Abnormalities of the LH receptor in 46,XX females will result in normal female sexual development and primary amenorrhea.²⁶ Serum LH may be normal to increased, FSH is normal, follicular phase estradiol levels are normal, and progesterone is low. The uterus is small and the ovaries are consistent with anovulation.

Gonadotropin-Releasing Hormone Receptor Abnormalities

Abnormalities of GnRH receptors have also been identified. The phenotype of GnRH resistance ranges from complete idiopathic hypogonadotropic hypogonadism to oligo-ovulation. Baseline levels of LH and FSH may be in the prepubertal or normal range. However, levels of other pituitary hormones, such as thyrotropin, growth hormone, prolactin, and corticotropin, are normal. Due to the failure to increase gonadal sex steroid secretion during puberty, secondary sex characteristics fail to develop and closure of the epiphyseal plates of the long bones is delayed, resulting in a eunuchoid habitus in which the arm span is greater than the height. Even in patients with complete forms, pulsatile GnRH administration may increase pituitary gonadotropin response; pregnancies have been reported.²⁷

Treatment

Treatment of isolated gonadotropin deficiency and receptor abnormalities will require low-dose estrogen (0.25 to 0.3 mg/day) to induce progressive pubertal maturation in a manner similar to Turner’s syndrome. Patients should be monitored at 2- or 3-month intervals to determine the rate of skeletal growth and development. After the first year, the addition of a progestin (medroxyprogesterone acetate, 5 mg/day) can be added for the last half of the month to induce menses and protect the endometrium from cancer. Once sexual maturation is completed, patients can be maintained on cyclic hormones or oral contraceptives.

Diagnostic Approach for Primary Amenorrhea

What Age?

An evaluation of primary amenorrhea is indicated when an adolescent fails to menstruate by age 15 in the presence of normal secondary sexual development (two standard deviations above the mean of 13 years), or within 5 years after breast development, if that occurred before age 10.² This age has recently been adjusted to a younger age, because girls are menstruating at a younger age. If there is a failure to initiate breast development by age 13 (two standard deviations above the mean of 10 years), an investigation should also be initiated.² These criteria are not absolute, and complete evaluation should be initiated if the patient presents with amenorrhea and obvious associated pathology such as cyclic pain or a blind vaginal pouch.

History and Physical Examination

A careful history is a key component to the evaluation and planning for the treatment of amenorrhea (Fig. 16-1). Special emphasis should be focused on physical or emotional stress, nutritional status, and history of genetic inherited disorders. The family should be questioned about familial disorders such as diabetes mellitus, previous medical disorders that may have been treated with gonadotoxic agents, and surgical disorders that involve the genital tract, including abnormal sexual differentiation. The functional inquiry should include secondary sexual development, galactorrhea, and the presence of hyperandrogenic symptoms.